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Halogen Bond Anion Templated Assembly of an Imidazolium Pseudorotaxane.

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DOI: 10.1002/ange.201001729
Halogen Bonding
Halogen Bond Anion Templated Assembly of an Imidazolium
Christopher J. Serpell, Nathan L. Kilah, Paulo J. Costa, Vtor Flix, and Paul D. Beer*
Halogen bonding is the noncovalent bonding interaction
between halogen atoms that function as electrophilic centers
(Lewis acids) and neutral or anionic Lewis bases.[1] Of the
many noncovalent interactions that are commonly utilized in
solid-state and solution supramolecular assemblies, halogen
bonding is arguably the least exploited, which is surprising
given its potentially powerful analogy to ubiquitous hydrogen
bonding.[2, 3] In fact, the use of halogen bonding as an
alternative or complement to hydrogen bonding in the
assembly of functional supramolecular materials is underexplored, having been largely restricted to the field of crystal
engineering.[4] In particular, halocarbons, for example iodoand bromoperfluorocarbons, have proved to be versatile
building blocks in the assembly of a diverse range of solidstate magnetic and conducting materials, and liquid crystals.[5?10] In addition, organic?inorganic networks that are
based on interactions between organic halogens (C X) and
inorganic metal halides and cyanides have been constructed.[11] Importantly, evidence of halogen bonding in the
solution phase is extremely rare.[12?14]
Stimulated by the fundamental roles that negatively
charged species play in a range of chemical, biological,
medical, and environmental processes, the field of anion
supramolecular chemistry has expanded enormously during
the past few decades. Numerous synthetic anion receptors,
which function by complementary electrostatic, hydrogen
bonding, Lewis acid?base, and anion?p noncovalent interactions, have been reported to date.[15?18] However, the
[*] C. J. Serpell, Dr. N. L. Kilah, Prof. P. D. Beer
Chemistry Research Laboratory, Department of Chemistry
University of Oxford
Mansfield Road, Oxford, OX1 3TA (UK)
Fax: (+ 44) 1865-272-690
recognition of anions in solution by halogen bonding is only
just beginning to be realized.[19?20] Inspired by natures
sophisticated highly selective sulfate- and phosphate-binding
proteins, we have used anion templation to construct elaborate interlocked host molecules. These unique three-dimensional topological cavities are designed to emulate natures
oxoanion binding site protein network of hydrogen bonds.
Halogen bonds are considered to be of comparable strength
to hydrogen bonds but have a more strictly linear geometry[21]
and different steric requirements. These properties make
halogen bonds an attractive supramolecular interaction to
integrate into and, importantly, potentially tune the selectivity
of interlocked binding pockets.
In a significant step towards incorporating halogen bonds
into interlocked host systems, we report herein the first
example of halogen bonding being exploited to facilitate
interpenetrative assembly by anion-templated pseudorotaxane formation. A halogen-functionalized imidazolium threading component is shown to interpenetrate an isophthalamide
macrocycle by chloride ion templation. Furthermore we
demonstrate that the stability of the interpenetrated assembly
is enhanced for the halogen-bonded pseudorotaxane as
compared to hydrogen-bonded pseudorotaxane analogues.
In addition, we also report a new hydrogen-bonding mode for
imidazolium pseudorotaxane assemblies.
In order to elucidate the halogen- and hydrogen-bonding
effects of anion-templated interpenetrative assemblies, a
series of potential threading bromo- and methyl-functionalized imidazolium derivatives were prepared (Scheme 1 and
Schemes S1, S2 in the Supporting Information). In particular,
varying the substitution pattern of the bromo and methyl
groups around the imidazolium motif would help delineate
Dr. P. J. Costa, Prof. V. Flix
Departamento Qumica, CICEO and
Sec紀 Autnoma de Ci辬cias da Sa?de
Universidade de Aveiro
3810-193 Aveiro (Portugal)
[**] C.J.S. thanks the EPSRC and Johnson Matthey for a CASE Studentship. N.L.K. thanks the Royal Commission for the Exhibition of 1851
for a research fellowship. P.J.C. thanks FCT for the postdoctoral
grant SFRH/BPD/27082/2006. V.F. acknowledges the FCT with coparticipation of the European Community funds FEDER, for
financial support under project PTDC/QUI/68582/2006. We thank
Oxford University Crystallography Service for instrument use.
Supporting information (full experimental details for synthetic
procedures, crystallographic analysis, 1H NMR spectroscopic
binding studies, and theoretical calculations) for this article is
available on the WWW under
Scheme 1. Imidazole starting materials and imidazolium salts.
2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2010, 122, 5450 ?5454
and establish the halogen bonding contribution to the overall
anion-templated pseudorotaxane assembly process.
4,5-Dimethylimidazole (1 b) was synthesized in a stepwise
procedure from 4-methyl-5-imidazolemethanol hydrochloride.[22] Bromination of 1 b and 1 c was achieved by reaction
with elemental bromine in the presence of potassium
carbonate, to give 1 d and 1 e.[23]
X-ray structural analysis of the bis(benzyl)imidazolium
bromide salts 2 d and 2 e confirmed anion coordination by
halogen bonding in the solid state (Figure 1). In both 2 d and
proton (labeled d) and the interior isophthalamide proton
(labeled c) resonances of the macrocycle occurred, which are
indicative of anion binding (Figure 2). Upfield movement of
the hydroquinone protons (labeled g and h) with concomitant
splitting caused by the proximal imidazolium ring current was
also observed, and is diagnostic of threading as opposed to
solely anion-binding (Figures S7?S12 in the Supporting Information). The addition of chloride ions in the noncoordinating
Figure 2. 1H NMR spectra of 4 (top) and 4 with 1.2 equivalents of 3 d
(bottom) in CDCl3. Proton assignments are given in Scheme 2.
Figure 1. X-ray crystal structures of 2 c, 2 d, 2 e, and 3 b. Thermal
ellipsoids set at 50% probability. Br brown, C gray, Cl green, H white,
N blue.
2 e, strong interactions are observed between the terminus of
the respective C Br bond and the bromide anion (RBr?Br =
0.86?0.89.[24] These interactions are essentially linear, with a
mean angle of 1748, which is consistent with a halogenbonded anion coordination system.[25, 26] Comparison of these
structures with those obtained for 2 c and the bis(hexyl)
chloride salt 3 b highlight the increased linearity of the
halogen bond, since the hydrogen-bonded systems have a
mean angle of 1538 at the protic hydrogen atom.
We have previously demonstrated that the chloride ion is
capable of templating the formation of pseudorotaxanes
between isophthalamide macrocycles and pyridinium, imidazolium, guanidinium, and triazolium threading components.[27, 28] We therefore chose the chloride ion as a potential
template for halogen-bonded interpenetrative assembly
bis(benzyl)imidazolium derivatives necessitated use of the
corresponding bis(hexyl)imidazolium chloride salt analogues
3 a?3 e in 1H NMR pseudorotaxane titration experiments,
which were conducted in CDCl3 with the isophthalamide?
hydroquinone macrocycle 4. Aliquots of imidazolium chloride salts 3 a?3 e, were added to a solution of 4. Typically, in
the case of 3 a?3 d, downfield progressions of the amide
Angew. Chem. 2010, 122, 5450 ?5454
Scheme 2. Halogen-bond-mediated anion-templated penetration of 3 d
through macrocycle 4.
tetrabutylammonium salt to 4 causes a downfield progression
of the hydroquinone protons (Figure S14 in the Supporting
Information). Pseudorotaxane assembly association constants
were calculated from the respective titration data using
WinEQNMR[29] (Table 1). There was good agreement
between values determined from titration data obtained by
monitoring the different protons of the macrocycle (see the
Supporting Information), thus indicating strong ion pairing
and interpenetration rather than anion binding.[27, 30]
2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Table 1: Association constants for 4 and 3 a?e.[a]
Ka [m 1]
3 a (imidazolium)
3 b (4,5-dimethyl)
3 c (2-methyl)
3 d (2-bromo)
3 e (4,5-dibromo)
3 d.PF6 (2-bromo)
92 (3)
97 (3)
245 (5)
254 (6)
[a] Values determined from amide proton titration data in CDCl3 and at
293 K. Errors are given in brackets.
The strongest pseudorotaxane assembly association was
observed when halogen bonding was employed with 2-bromoimidazolium chloride thread 3 d (Scheme 2); remarkably,
more than double the value of the hydrogen-bonded equivalent 3 b was obtained (Table 1). The occurrence of a halogenbonded anion templation mechanism rather than improved
p?p stacking was confirmed by comparison with the analogous hexafluorophosphate salt 3 d-PF6, which showed no
interaction with the macrocycle.
Importantly, the pseudorotaxane formation behavior of
the other potential imidazolium chloride threading components serves to further highlight the differences between
hydrogen and halogen bonding. The behavior of 3 b was
almost identical to that of 3 a, and is consistent with chloride
ion hydrogen bonding in unsubstituted imidazolium systems
occurring primarily through the acidic 2-position. However,
the 2-methyl-imidazolium thread 3 c formed a much more
stable pseudorotaxane assembly (Table 1). This result indicates that the comparative directional flexibility of hydrogen
bonds allows a cooperative chelating hydrogen-bonding mode
to the chloride anion through the 4 and 5 positions, which is
beneficial for threading. The change in orientation is further
corroborated by a clear diagnostic change in the pattern of
hydroquinone shifts during the titration, characteristic of a
qualitative difference in the p?p stacking motif (Figure 3 and
Figures S9, S10 in the Supporting Information). Different
shifting effects were also observed for the imidazolium methyl
protons, thus suggesting that improved C H贩稯 hydrogen
bonding to the polyether macrocycle of 4 may also assist the
formation of 4�c (Figure S15 in the Supporting Information).
Figure 3. Pseudorotaxanes 4�b and 4�c.
It is noteworthy that this hydrogen-bonding directional
elasticity was not seen with the halogen-bonded analogue 3 e,
which displayed no affinity for the macrocycle. The dramatic
impact of the requirement of linearity in halogen bonding
does not allow for a chelation effect with divergent C Br
bonds; this observation is also consistent with crystallographic
and theoretical calculations.[21] Thus the pseudorotaxane
assembly is not formed with 3 e.
Further evidence for halogen-bond mediated anion-templated interpenetration to form 4�d in the solution phase was
obtained by 1H ROESY NMR spectroscopy (Figures S16?S19
in the Supporting Information). This experiment showed that
a number of through-space interactions occur between 3 d and
the macrocycle, thus confirming both pseudorotaxane formation and orientation of the thread within the macrocycle
cavity, which is consistent with the halogen-bonding model.
The anion-templated assembly of pseudorotaxane 4�d
mediated by halogen bonding was further investigated by
means of combined molecular dynamics and density functional theory calculations (see the Supporting Information for
full details). The DFT-optimized structure of 3 d (Figure S20
in the Supporting Information) shows a C Br贩稢l interaction with an equilibrium distance of 2.62 (RBr?Cl = 0.73) and
an angle of 1798, which is consistent with the X-ray structures
of 2 d and 2 e and the expected directional linearity of the
halogen bond.[21] Furthermore, the C?Br distance in 3 d is
slightly longer (1.99 ) than that found in the imidazolium
thread without the chloride ion (3 d*; 1.86 ). The nature of
this type of halogen bonding was elucidated by Clark et al.,[31]
who introduced the term ?s-hole? to describe the positive
surface region of the halogen atom capable of establishing
interactions with electron-rich sites. This concept is precisely
illustrated with the calculated molecular electrostatic potential surfaces of 3 d and 3 d* (Figure 4). In 3 d the chloride ion is
Figure 4. Molecular electrostatic potential surfaces for a) 3 d and
b) 3 d* (right). The color ranges are from red (more negative sites)
< yellow < green < blue(more positive sites), scales normalized.
clearly negative (Figure 4 a; shown in red), the intermolecular
region is shown in yellow and the Br atom is slightly positive
(Figure 4 b; shown in green). However, in the ?chloride-free?
imidazolium derivative 3 d*, the negative charge density is
more concentrated on the two hexyl alkane tails and the
bromine atom is slightly positive, with a more positive area at
the tip (colored blue). This positive charge enables the
interaction with the chloride ion.
Having established that there is a stable C Br贩稢l
halogen bond in 3 d, we then focused on the study of the
anion-templated interpenetrated structure 4�d. As this
pseudorotaxane has a large conformational freedom, we
performed a conformational analysis with quenched molec 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. 2010, 122, 5450 ?5454
ular dynamics, which uses a combined molecular dynamics/
molecular mechanics (MD/MM) approach. The lowest energy
coconformation obtained by MD/MM (4�d-A) was then
DFT-optimized (Figure 5). The C Br贩稢l halogen-bond
Figure 5. DFT-optimized structure of 4�d (co-conformation 4�d-A)
showing the linear C Br贩稢l halogen bond (black dashed line) and
the N H贩稢l hydrogen bonds (yellow dashed lines). Br brown, C gray,
N blue, O red. Imidazolium alkyl chains are shown in orange, and the
chloride ion is shown as a green sphere.
interaction is present with a distance of 2.92 (RBr?Cl =
0.81) and a bond angle of 174.88. As observed for other
related pseudorotaxane systems,[27] the imidazolium derivative also partakes in charge-assisted p-stacking interactions
with the hydroquinone units of macrocycle 4. The chloride
anion establishes hydrogen bonds with the amide protons of
the isophthalamide with H贩稢l distances 2.50 and 2.49 .
The strength of the C Br贩稢l interaction in 3 d and
4�d-A was evaluated through a natural bond order (NBO)
population analysis carried out for these two molecules and
3 d* (Table S1 in the Supporting Information).[32] These
studies demonstrate that the magnitude of the ?s-hole? in
3 d*, 3 d, and 4�d is greater than that in CF3Br. The natural
charges calculated for these compounds (Table S1 in the
Supporting Information) follow the same trend. Wiberg bond
indices (WI)[33] were also calculated (Table S2 in the Supporting Information). The C Br distance in 3 d is longer and the
respective WI is smaller than in 3 d*, thus implying that this
bond is weakened by the C Br贩稢l interaction whose WI is
rather large (0.3401), almost half of the respective C Br value
(0.8477). Although halogen bonds are normally considered to
be noncovalent interactions, the relatively large WI indicates
that the C Br贩稢l interaction is strong, with relevant
covalent character. The covalent contribution for strong
halogen bonds was previously identified, based on ab initio
and quantum theory of atoms in molecules (QTAIM)
analysis, by Zou and co-workers.[34] On forming the pseudorotaxane 4�d-A, the C Br bond becomes stronger (WI =
1.0248), whereas the C Br贩稢l halogen bonding is weakened
(WI = 0.1335) because of the new N H贩稢l interaction.
Nonetheless, the C Br贩稢l interaction is still strong enough
to maintain the pseudorotaxane arrangement, which is
consistent with the experimental data. In summary, all
calculations support the formation of the pseudorotaxane
Angew. Chem. 2010, 122, 5450 ?5454
4�d assembly assisted by a combination of C Br贩稢l and
N H贩稢l bonds with charge-assisted p-stacking interactions.
In conclusion, halogen bonding has been exploited for the
first time in the assembly of an interpenetrated molecular
system. Halogen bonding has been demonstrated to effect
and enhance the strength of chloride ion templated pseudorotaxane formation between a 2-bromo-functionalized imidazolium threading component and an isophthalamide macrocycle, as compared to hydrogen-bonded pseudorotaxane
analogues. In addition, whereas a cooperative 4,5-imidazolium hydrogen-bonding chloride ion chelation effect facilitates the formation of pseudorotaxane 4�c, the strongly
linear nature of halogen bonding negates such a cooperative
effect taking place with 4,5-dibromoimidazolium chloride
derivative 3 e, and, as a consequence, interpenetration does
not occur. Work toward the construction of interlocked
halogen-bonded host systems for anion recognition applications is currently underway.
Received: March 23, 2010
Published online: June 22, 2010
Keywords: anions � halogen bonding � pseudorotaxanes �
supramolecular chemistry � template synthesis
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bond, imidazoline, assembly, halogen, pseudorotaxane, anion, template
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